Aziridines are organic compounds having a 3-member ring with a large distortion. The general formula of an aziridine moiety is shown below:

The incorporation of an aziridine into an organic compound is referred to as aziridination. Aziridination is a powerful approach for introducing nitrogen into organic compounds, especially olefins (Müller, P. et al. (2003) “ENANTIOSELECTIVE CATALYTIC AZIRIDINATIONS AND ASYMMETRIC NITRENE INSERTIONS INTO CH BONDS,” Chem. Rev. 103(8); 2905-2920; Dauban, P. et al. (2003) “IMINOIODANES AND C—N BOND FORMATION IN ORGANIC SYNTHESIS,” Synlett 2003:1571; Jacobsen, E. N. (1999) “FUTURE PERSPECTIVES IN ASYMMETRIC CATALYSIS,” 2:607, In: Comprehensive Asymmetric Catalysis; Jacobsen, E. N. et al. Eds., Springer-Verlag, Berlin; Müller, P. (1997) “TRANSITION METAL-CATALYZED NITRENE TRANSFER: AZIRIDINATION AND INSERTION,” 2:113, In: Advances in Catalytic Processes; Doyle, M. P., Ed; JAI Press Inc, Greenwich). Largely regarded for their synthetic versatility, aziridines are well suited for ring opening with an assortment of nucleophiles to yield functionalized amines (Hu, X. E. (2004) “NUCLEOPHILIC RING OPENING OF AZIRIDINES,” Tetrahedron 60:2701).
Several methods for directly forming aziridines have been advanced. U.S. Pat. No. 4,840,890 (Kamei et al.), for example, teaches that such compounds can be produced through the intramolecular dehydration of an alkanolamine. U.S. Pat. No. 5,929,252 (Sharpless et al.) discloses that phenyltrimethylammonium tribromide may be employed as a general catalyst for the direct aziridination of olefins. U.S. Pat. No. 5,703,246 (Aggarwal et al.) teaches forming aziridines by reacting a metallocarbon with an alkyl, aryl or heteroaromatic sulfide and then reacting the product with an amide, carbonyl, or olefin. Ylides have been used to catalyze aziridination (Doyle, M. P. et al. (2001) “Epoxides and aziridines from diazoacetates via ylide intermediates,” Org. Lett. 3(6):933-935; Yang, X. F. et al. (2002) “STEREOCONTROLLED AZIRIDINATION OF IMINES VIA A SULFONIUM YLIDE ROUTE AND A MECHANISTIC STUDY,” J. Org. Chem. 67(23):8097-8103). Electrochemical approaches to aziridination have been proposed (Hilt, G. (2002) “DIRECT ELECTROCHEMICAL AZIRIDINATION OF ALKENES UNDER METAL-FREE CONDITIONS,” Angew Chem Int. Ed. Engl. 41(19):3586-3588, 3513). Iodine (III) has been used to mediate aziridination (Padwa, A. et al. (2002)“STEREOCHEMICAL ASPECTS OF THE IODINE(III)-MEDIATED AZIRIDINATION REACTION OF SOME CYCLIC ALLYLIC CARBAMATES,” Org. Lett. 4(13):2137-2139). Mahoney, J. M. et al. (2005) disclose the use of Brønsted Acids to catalyze aziridination (BRØNSTED ACID-PROMOTED OLEFIN AZIRIDINATION AND FORMAL ANTI-AMINOHYDROXYLATION,” J. Am. Chem. Soc. 127:1354-1355). U.S. Pat. No. 6,258,960 (Antilla et al.) teaches the synthesis of chiral cis-aziridines by reacting an imine with a diazo compound in the presence of a chiral vaulted biary-Lewis Acid complex. U.S. Pat. No. 6,307,087 (Buchwald et al.), U.S. Pat. No. 6,395,916 Buchwald et al.) and U.S. Pat. No. 6,946,560 (Buchwald et al.) disclose Ar—Ar1 compounds, where Ar and Ar1 are optionally substituted monocyclic and polycyclic aromatic and heteroaromatic moieties, and the compounds are produced through the use of a transition metal (including rhodium) and a ligand that may contain an aziridine moiety.
Methods of using aziridines are disclosed in U.S. Pat. No. 5,936,127 (Zhang). U.S. Pat. No. 4,026,709 (Piller et al.) discloses uses of aziridines in facilitating the synthesis of photographic color couplers. U.S. Pat. No. 5,712,331 (Ryang) teaches the use of poly N-substituted aziridines to form curable resins. U.S. Pat. No. 5,936,127 (Zhang) teaches the aziridination of aldehydes as a means for producing chiral heterocyclic compounds.
Despite their value and utility, available methods for the direct preparation of aziridines remain limited. Transition metal catalyzed processes in conjunction with an appropriate nitrene precursor (e.g., iminophenyliodinanes such as TsN=IPh, or in situ variants) have received considerable attention, and represent the best currently available technology for forming aziridine derivatives (Dauban, P. et al. (2001) “COPPER-CATALYZED NITROGEN TRANSFER MEDIATED BY IODOSYLBENZENE PHI=O,” J. Am. Chem. Soc. 123:7707-7708; Duran, F. et al. (2002) “INTRAMOLECULAR PHI=O MEDIATED COPPER-CATALYZED AZIRIDINATION OF UNSATURATED SULFAMATES: A NEW DIRECT ACCESS TO POLYSUBSTITUTED AMINES FROM SIMPLE HOMOALLYLIC ALCOHOLS,” Org. Lett. 4:2481-4283; Gillespie, K. M. et al. (2002) “ENANTIOSELECTIVE AZIRIDINATION USING COPPER COMPLEXES OF BIARYL SCHIFF BASES,” J. Org. Chem. 67(10):3450-4588; Siu T. et al. (2002) “PRACTICAL OLEFIN AZIRIDINATION WITH A BROAD SUBSTRATE SCOPE,” J. Am. Chem. Soc. 124:530-531; Li, Z. et al. (1993) “ASYMMETRIC ALKENE AZIRIDINATION WITH READILY AVAILABLE CHIRAL DIIMINE-BASED ZCATALYSTS,” J. Am. Chem. Soc. 115:5326-5327; Evans, D. A. et al. (1994) “DEVELOPMENT OF THE COPPER-CATALYZED OLEFIN AZIRIDINATION REACTION,” “J. Am. Chem. Soc. 116:2742-2753; Sanders, C. J. et al. (2000) “STRUCTURAL ORIGINS OF A DRAMATIC VARIATION IN CATALYST EFFICIENCY IN ENANTIOSELECTIVE ALKENE AZIRIDINATION: IMPLICATIONS FOR DESIGN OF LIGANDS BASED ON CHIRAL BIARYLDIAMINES,” J. Am. Chem. Soc. 122:7132-7133; Liang, J.-L. et al. (2002) “METALLOPORPHYRIN-MEDIATED ASYMMETRIC NITROGEN-ATOM TRANSFER TO HYDROCARBONS: AZIRIDINATION OF ALKENES AND AMIDATION OF SATURATED C—H BONDS CATALYZED BY CHIRAL RUTHENIUM AND MANGANESE PORPHYRINS,” Chem. Eur. J. 8:1563) for which catalysis via dirhodium(II,II) complexes (Rh24+) holds a prominent position (Müller, P. et al. (1996) “A METHOD FOR RHODIUM(II)-CATALYZED AZIRIDINATION OF OLEFINS,” Tetrahedron 52:1543; Müller, P. et al. (1998) “THE RHODIUM(II)-CATALYZED AZIRIDINATION OF OLEFINS WITH\{[(4-NITROPHENYL)SULFONYL]IMINO\}PHENYL-BOLD LAMBDA 3-IODANE,” Can. J. Chem. 76:738-750; Guthikonda, K. et al. (2002) “A UNIQUE AND HIGHLY EFFICIENT METHOD FOR CATALYTIC OLEFIN AZIRIDINATION,” J. Am. Chem. Soc. 124:13672; Liang, J.-L. et al. (2002) “RHODIUM(II,II) DIMER AS AN EFFICIENT CATALYST FOR AZIRIDINATION OF SULFONAMIDES AND AMIDATION OF STEROIDS,” Org. Lett. 4:4507; Liang, J. L. et al. (2003) “CHIRAL RHODIUM(II,II) DIMERS CATALYZED ENANTIOSELECTIVE INTRAMOLECULAR AZIRIDINATION OF SULFONAMIDES AND CARBAMATES,” Tetrahedron Lett. 44:5917; Fruit, C. et al. (2004) “ASYMMETRIC TRANSFER OF NITRENES CATALYZED BY CHIRAL DIRHODIUM(II) USING AROMATIC SULFAMATE ESTERS,” Tetrahedron-Asymmetry 15:1019). However, drawbacks in the uses of this methodology arise from high catalyst loadings, limited shelf life of TsN=IPh, competing C—H insertion, and/or poor selectivity.
Ruthenium, silver and copper catalysts have been studied in efforts to mediate more efficient direct aziridination (Man, W. L. et al. (2004) “DIRECT AZIRIDINATION OF ALKENES BY A CATIONIC (SALEN)RUTHENIUM(VI) NITRIDO COMPLEX,” J. Am. Chem. Soc. 126(47):15336-15337; Omura, K. et al. (2004) “DESIGN OF A ROBUST RU(SALEN) COMPLEX: AZIRIDINATION WITH IMPROVED TURNOVER NUMBER USING N-ARYLSULFONYL AZIDES AS PRECURSORS,” Chem. Commun. (Camb) 21(18):2060-2061; Cui, Y. et al. (2003) “EFFICIENT AZIRlDINATION OF OLEFINS CATALYZED BY A UNIQUE DISILVER(I) COMPOUND,” J. Am. Chem. Soc. 125(52):16202-16203; Gullick, J. et al. (2003) “OBSERVATION OF THE ENHANCEMENT IN ENANTIOSELECTIVITY WITH CONVERSION FOR THE AZIRIDINATION OF STYRENE USING COPPER BIS(OXAZOLINE) COMPLEXES,” Chem. Commun. (Camb.) (22):2808-2809. Rhodium (II,II) dimers have also been reported as aziridination catalysts (Liang, J. L. et al. (2002) “RHODIUM(II,II) DIMER AS AN EFFICIENT CATALYST FOR AZIRIDINATION OF SULFONAMIDES AND AMIDATION OF STEROIDS,” Org. Lett. 4(25):4507-4510).
Unfortunately, despite all such advances, methods for directly forming aziridines remain of limited utility, due to yield, cost, complexity or lack of stereospecificity. Thus, a need remains for a chemical synthetic approach capable of efficiently forming aziridines and possessing stereospecific control. The present invention is directed to this and other needs. The present invention is thus directed to a mild, selective, and efficient aziridination protocol that involves catalysis by a mixed-valent dirhodium(II,III) catalyst (Rh25+).